In vitro and in vivo studies of enzyme-digestible hydrogels for oral drug delivery

Abstract

Gastric retention of enzyme-digestible hydrogels in dogs was studied to develop a platform for longterm oral drug delivery. The movements of hydrogels in the canine stomach and the gastric tissue-hydrogel interactions were visualized in real-time using three imaging techniques: radiography, fluoroscopy, and 2-D ultrasonography. Hydrogels with appropriate size and integrity were retained in the stomach for more than 24 h even under fasted conditions. Gastric retention was prolonged up to 60 h when the 24 h-fasted state was followed by a once-a-day pelletized meal. In vitro drug release from enzyme-digestible hydrogels was examined. The hydrogels were loaded with flavin mononucleotide (FMN) and air-dried for 7 days. FMN was released from the gels in the simulated gastric juice for up to 454 h and 650 h in the presence and absence of pepsin, respectively. About 90% of the loaded FMN was released in 300 h. During this time, the presence of pepsin in the solution did not make any significant difference in the release profiles. When the FMN-containing hydrogels were administered to dogs, the blood concentration of FMN was maintained at the level of 0.75 μg/ml for 24 h under fasted conditions. In each experiment, the presence of a hydrogel in the stomach was confirmed using the three imaging techniques. When the 24-h-fasted state was followed by a once-a-day meal, appreciable FMN concentration was detected in the blood for up to 54 h. This study showed that once-a-day oral drug delivery is possible even with a drug which is absorbed only from the upper small intestine and has a short half-life.